Key result
Administration of allopregnanolone selectively reduced mean arterial pressure (-8.0 ± 2.7 mmHg; P=0.02) and the depressor response to pentolinium in BPH/2J mice.
Why the study?
Does allopregnanolone reduce mean arterial pressure in Schlager hypertensive mice?
Does allopregnanolone reduce mean arterial pressure in Schlager hypertensive mice?
Effect estimate: -8.0 ± 2.7 mmHg
p-value: p=0.02
Positive allosteric modulation of GABAA receptors with allopregnanolone attenuates high blood pressure and stress responses in a neurogenic hypertension mouse model.
Hypothesis-generating for GABAA modulation in neurogenic hypertension; leaves open translation to human disease.
OBJECTIVE: Blood pressure high Schlager (BPH/2J) mice have neurogenic hypertension associated with differences in hypothalamic GABAA receptors compared with their normotensive counterparts (BPN/3J). Allopregnanolone is an endogenous neurosteroid reduced in chronic stress, and when administered, decreases anxiety by positive allosteric modulation of GABAA receptors. METHODS: To determine if allopregnanolone could be a viable therapeutic for neurogenic hypertension, male BPH/2J (n = 6-7) and BPN/3J (n = 8-9) mice were equipped with radiotelemetry probes to compare cardiovascular variables before and after implantation of subcutaneous minipumps delivering allopregnanolone (5 mg/kg per day), or its vehicle, for a period of 2 weeks. In addition to baseline recordings, the response to stress and ganglionic blockade with pentolinium was recorded, before and 7-14 days after minipump implantation. Following treatment, brains were processed for c-Fos immunohistochemistry and quantitative real-time polymerase chain reaction. RESULTS: Administration of allopregnanolone selectively reduced mean arterial pressure (-8.0 ± 2.7 mmHg; P = 0.02) and the depressor response to pentolinium (-15.3 ± 3.2 mmHg; P = 0.001) in BPH/2J mice, with minimal effects observed in BPN/3J mice. Following allopregnanolone treatment, the diminished expression of GABAA δ, α4 and β2 subunits in the hypothalamus (-1.6 to 4.8-fold; Pstrain < 0.05) was abolished. Furthermore, in BPH/2J mice, allopregnanolone treatment reduced the pressor response to dirty cage switch stress (-26.7 ± 4.5%; P < 0.001) and abolished the elevated c-Fos expression in pre-sympathetic nuclei. CONCLUSION: The selective antihypertensive and stress inhibitory effects of allopregnanolone in BPH/2J mice suggest that allosteric modulation of GABAA receptors, in amygdalo-hypothalamic pathways, may contribute to the development of hypertension in this model and may offer a potential new therapeutic avenue.
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Stevenson et al. (2016) studied Neurogenic hypertension. Allopregnanolone vs. Vehicle was evaluated on Mean arterial pressure (-8.0 ± 2.7 mmHg, p=0.02). Administration of allopregnanolone selectively reduced mean arterial pressure (-8.0 ± 2.7 mmHg; P=0.02) and the depressor response to pentolinium in BPH/2J mice.
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